Cleveland: In a combination of both clinical studies of over 4,000 patients and animal model studies, Cleveland Clinic researchers have demonstrated -- for the first time -- that gut microbes alter platelet function and risk of blood clot-related illnesses like heart attack and stroke.

When the nutrient choline -- which is abundant in animal products like meat and egg yolk -- is ingested, gut microbes play a role in breaking it down and producing the compound TMAO. High levels of TMAO have been linked to heart disease in recent studies. The studies showed that blood TMAO levels are associated with heightened risk of heart attacks and strokes in humans, even after adjusting for traditional cardiac risk factors, renal function, markers of inflammation, medication use, and cardiovascular disease status.

The new study -- to be published in Cell's March 10, 2016 online edition and March 24 print edition -- shows that TMAO directly alters platelet function, increasing thrombosis (blood clot) potential, which could potentially be the mechanism by which TMAO increases heart attack and stroke risk. These findings reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.

"It is remarkable that gut microbes produce a compound that alters platelet function and thrombotic heart attack and stroke risk," said lead author Stanley Hazen, M.D., Ph.D., chair of the Department of Cellular & Molecular Medicine in the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic "This new link helps explain how diet-induced TMAO generation is mechanistically linked to development of lethal adverse complications of heart disease. The results of the studies suggest potential new therapeutic targets and possible nutritional interventions for preventing cardiovascular events and improving heart health."

This latest discovery further adds to the growing body of data showing a link between TMAO, gut microbes, and heart disease. It also shows that lowering TMAO may represent a potential new way to reduce the formation of blood clots, and therefore decrease the risk of cardiovascular events like heart attacks and strokes. Heart disease is the No. 1 killer in the world of both men and women.

The link between TMAO, gut microbes and heart disease was first discovered five years ago by the same investigative team, led by Dr. Hazen. Weifei Zhu, Ph.D., and Jill Gregory,Ph.D. are co-first authors on the current manuscript, and are also members in the Department of Cellular & Molecular Medicine in the Lerner Research Institute.

In this study, researchers analyzed blood levels of TMAO in over 4,000 patients and saw a significant correlation between higher TMAO and thrombosis potential. This generated the hypothesis that TMAO may directly impact platelet function. Subsequent studies with both human platelets and animal models confirmed that TMAO makes platelets over-reactive, heightening thrombosis potential and accelerating clotting rates. Enhanced platelet responsiveness and clot formation is the culminating event that causes a heart attack or stroke, which account for the majority of deaths worldwide.

"We have shown that TMAO fundamentally alters calcium signaling within platelets; when TMAO is elevated, platelet responsiveness to known triggers like thrombin, collagen or ADP is heightened," Hazen said. "In general, there's a broad range for how quickly different people will form clots. However, across the board, when TMAO is elevated, platelet responsiveness jumps to the hyper-reactive side of normal."

Microbial transplantation studies showed TMAO production and thrombosis potential are transmissible traits, building on the recent demonstration that atherosclerosis susceptibility similarly can be transmitted from donor to recipient with transfer of gut microbes via TMAO production potential.

According to the Centers for Disease Control and Prevention, heart disease kills about 610,000 in the United States annually, accounting for one in every four deaths.

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This research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements.

About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, eight community hospitals, more than 90 northern Ohio outpatient locations, including 18 full-service family health centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and Cleveland Clinic Abu Dhabi. In 2014, there were 5.9 million outpatient visits throughout the Cleveland Clinic health system and 152,500 hospital admissions. Patients came for treatment from every state and 147 countries. Visit us at http://www.clevelandclinic.org. Follow us at http://www.twitter.com/ClevelandClinic.

About the Lerner Research Institute

The Lerner Research Institute (LRI) is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. In 2015, LRI researchers published nearly 600 articles in high-impact biomedical journals (top 10% of all biomedical journals). LRI's total annual research expenditure was $251 million in 2015 (with $104 million in competitive federal funding). Approximately 1,200 people (including approximately 150 principal investigators, 200 research fellows, and about 100 graduate students) in 12 departments work in research programs focusing on cardiovascular, cancer, neurologic, musculoskeletal, allergic and immunologic, eye, metabolic, and infectious diseases. The LRI has more than 700,000 square feet of lab, office, and scientific core services space. LRI faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University - training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The LRI is a significant source of commercial property, generating 54 invention disclosures, 14 licenses, and 76 patents in 2015.

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